Device for the desynchronization of neuronal brain activity

ABSTRACT

A device for desynchronizing neuronal brain activity involving a neuron population firing in a synchronized manner at a pathological frequency. The device includes an electrode configured to generate stimuli that stimulate the neuron population; and a control unit configured to control the electrode to generate the stimuli in sequence, wherein the stimuli succeed each other with a predetermined frequency f. The predetermined frequency f is substantially equal to g×n/m, where g is the pathological frequency, and n and m are integers.

The invention relates to a device for the desynchronization of neuronalbrain activity in accordance with the preamble of claim 1.

In patients with neurological or psychiatric disorders, for exampleParkinsonism (Morbus Parkinson), essential tremor, dystony or obsessivedisorders, nerve cell groups or networks in circumscribed regions of thebrain, for example the thalamus and the basal ganglia, becomepathologically active, for example, excessively synchronous in theiractivity. In this case a large number of neurons generate actionpotentials synchronously. The neurons involved fire predominantlysynchronously. With healthy individuals, by contrast, the neurons inthese regions of the brains fire qualitatively differently, for examplein an uncontrolled manner.

In the case of Morbus Parkinson, the pathological synchronous activityfor example of the thalamus and the basal ganglia, alter the neuronalactivity in other grain regions, for example in areas of the cerebralcortex like the primary motor cortex. In that case, the pathologicalsynchronous activity in the region of the thalamus and the basal gangliahas its rhythm impressed upon the cerebral cortex so that the musclescontrolled by this region undergo pathological activity, for example, arhythmic trembling (tremor).

In patients who no longer can be effectively treated by medication,depending upon the pathological patterns and whether the pathologyarises from one side or both sides of the brain, a deep electrode can beimplanted on one or both sides. A cable runs under the skin from thehead to a so-called generator which comprises a control device and abattery and for example can be implanted under the skin in the region ofthe clavicle. Through the deep electrodes a continuous stimulation isapplied with a high frequency periodic pulse sequence (pulse train witha frequency of >100 Hz) of individual pulses, for example rectangularpulses. The goal of this method is to suppress the firing of the neuronsin the target regions. The mechanism by which this operates in standardstimulation has not been sufficiently clarified as yet. The results ofmultiple studies suggest that the standard deep stimulation operateslike a reversible leisioning, that is a reversible switch off of thetissue: the standard deep stimulation suppresses the firing of theneurons in the target regions and/or in the brain regions connectedtherewith.

A disadvantage with this manner of stimulation is that the energyconsumption of the generator is very high so that the generator,including its batteries must be replaced by an operative procedurerelatively early, after about one to three years. Of even greaterdrawback is that the high frequency continuous stimulation isunphysiological (unnatural) input in the region of the brain for examplethe thalamus or the basal ganglia which in a few years can give rise toadaptation of the impacted nerve cell networks. In order to produce thesame stimulation results, therefore, to overcome this adaptation, higherstimulation amplitudes must be used. The greater the stimulationamplitude, the greater is the probability that as a consequence andstimulation, neighboring areas will be subjected to collateral effectsor damage like dysarthria (speech disturbances), dysaesthesis (in partfrom painful missynesthesia), cerebral ataxy (instability, inability tostand without assistance) or schizophrenic like symptoms, etc. Theseside effects cannot be tolerated by patients. The treatment, thereforeloses its effectiveness in these cases after several years.

As a consequence, another method has been proposed as is described inthe German Patent Document DE 102 11766.7 “Device for the Treatment ofPatients by Means of Brain Stimulation, An Electronic Unit As Well AsThe Use of the Device and the Electronic Unit in Medicine”, in which thedemand-controlled excitation is applied to respective target regions inwhich pathologically synchronized numonal activity is to bedesynchronized. The goal of this method/this device is not simply tosuppress the pathologically synchronous firing as with standard deepstimulation but to approximate the physiological uncorrelated firingpatterns. In this manner on the one hand the current consumption can bereduced and on the other hand, adaptation processes of the nerve tissuewhich can require an increase in the stimulation amplitude and give riseto side effects, can be prevented. This demand controlleddesynchronization method has however also relevant drawbacks.

Drawbacks of the demand-controlled or need-controlled desynchronizationstimulation method of DE 102 117 66.7 results from the followingconsiderations:

In order to desynchronize a synchronized nerve cell network with anelectric stimulus, an electrical stimulus of a certain duration must beapplied at a certain phase of the pathological rhythmic activity in thetarget area with precision. Since such a precision cannot be readilydetermined experimentally at the present time, combinations of stimuliare used. A first stimulus or excitation pulse of such a compositestimulus controls the dynamics of the population to be desynchronized bya reset, that is a new start, while the second excitation of thecomposite stimulus encounters and desynchronizes the nerve cell group ina vulnerable state it is however unavoidable in this connection, toensure that the quality of the control, that is the quality of thereset, to provide a stronger stimulus for the reset. This should howeverbe avoided in the sense of minimizing side effects. It is decisive tothis end that the desired desynchronizing effect can only arise when thestimulation parameters, thus the duration of the individual excitationsand especially the pause between the first and second excitations areoptimally selected. This has severe consequences:

1. A time consuming calibration procedure is required which typicallylasts longer than 30 minutes

2. As a consequence of the time consuming calibration procedure, theeffect of desynchronizing simulation in accordance with DE 102 117 66.7cannot be made part of an intraoperative selection of the appropriatetarget point for the insertion of the deep electrode. For that purposethe effect of the desynchronization stimulation according to DE 102117.66.7 must be tested separately for different target points since foreach target point a separate calibration is required. This woulddecrease the duration of electrode implantation surgery for a patient ina prohibitive manner.

3. With large variations in the network characteristics, that isfluctuations in the parameters which describe the activity of the nervecell population like, for example, synaptic amplitude and firing rate,new calibrations are required which means that during the calibration,no therapeutic effect can be produced.

4. Since the desynchronizing stimulation according to DE 102 66.7 canonly be effective when the frequency of the neuron population to bedesynchronized does not have large fluctuations, this stimulation cannotbe used with pathologies in which the pathologically excessivelysynchronized activity arises for only brief periods of time and thenwith strongly varying frequencies as for example in the case ofepilepsy.

It is, therefore, the object of the invention to provide a device forthe desynchronization of neuronal brain activity with which theadaptation to a nonphysiological continuous stimulation can besuppressed in the treatment of patients with electrode stimulation. Itshould eliminate the need for lengthy and wearing calibration proceduresand permit the stimulation even in the case when the main frequencycomponents of the pathologically rhythmic activity is subject to largefluctuations. The stimulation device according to the invention shouldfunction in an electric power conserving manner so that the batteriesimplanted in the patient seldom require operative replacement.

Starting from the preamble of claim 1, the objects are achievedaccording to the invention by the features given in the characterizingpart of claim 1. Surprisingly, the objects are achieved in that at leasttwo partial regions of a brain area or at least two functionallyassociated brain areas are each respectively reset in their activitywith at least two electrodes, that is reset with respect to otherphases, whereby for an ill person surprisingly a desynchronization isfound in the relevant neuron populations and the illness symptomaticallysuppressed.

With the device according to the invention it is thus possibleimmediately and directly to treat patients by means of a multielectrodestimulation, (I) without thereby an adaptation arising to anonphysiological continuous stimulation, (ii) without the need for alengthy and wearing calibration procedure, (iii) and even when the mainfrequency components of the pathological rhythmic activity are subjectedto strong fluctuations.

As a consequence, the above mentioned side effects can be reduced orsuppressed. The device according to the invention enables the effect ofthe desynchronization stimulation intra operatively applied by selectionof the most suitable target point for the deep electrode, to be utilizedfor this purpose, during the implantation of the deep electrode in theregion of the anatomically precalculated target point, the deviceaccording to the invention applies test stimuli as the deep electrode ismoved in millimeter steps. The target point at which the besttherapeutic effect will be produced in this test stimulation mode isselected as the target point for the permanent implantation. Inaddition, apart from the aforementioned illnesses which are associatedmainly with pathologically synchronized activity with relativelyconstant frequencies, illnesses can be treated with which onlyintermittent (briefly arising) pathologically synchronous activity isassociated. A main indication is therefore the treatment of epilepticswho can no longer be treated by medication. The device of the inventioncan be used for example for illnesses like Morbus Parkinson, essentialtremor, dystony, epilepsy and obsessive disorders where adesynchronization may be of interest.

The device of the invention operates in an electric current conservingmanner so that the batteries implanted in the patient seldom requirereplacement.

Advantageous features of the invention are given in the dependentclaims.

The figures show exemplary embodiments of the invention.

They show:

FIG. 1: a device according to the invention.

FIG. 2: the time course of the amplitude of the local field potentialmeasured by the sensor 3 during the demand-controlled timing.

FIG. 2 b: the time course of the discharge pattern measured via sensor 3of the nerve cells during the demand controlled timing.

FIG. 3 a: the time course of the amplitude of the local field potentialmeasured by sensor 3 during recurrent application with demand controlexcitation or stimulation amplitude.

FIG. 3 b: the time course of the discharge patterns of the nerve cellsmeasured by sensor 3 during recurrent application with demand controlstimulation amplitude.

FIG. 4 a through 4 d: an example of an excitation application with fourelectrodes.

FIG. 5 a through 5 d: an example of a time offset application ofidentical high frequency pulse trains to four electrodes.

The device according to FIG. 1 comprises an isolating amplifier 1connected to at least two electrodes 2 and sensors 3 for detecting thephysiological measurement signals. The isolating amplifier is alsoconnected with a unit for signal processing and control which isconnected to an optical transmitter for the simulation 5. The opticaltransmitter 5 is connected by a light waveguide or conductor 6 with anoptical receiver 7 which in turn is connected with a stimulator unit 8for stimulation. The stimulator unit 8 for stimulation is connected withat least two electrodes. At the inlet region, to the isolating amplifier1 at which the electrodes 2 are connected, there is a relay 9 or atransistor. The unit 4 is connected via a line 10 with a telemetrytransmitter 11 which communicates with a telemetry receiver 12 locatedexternally of the device to be implanted and providing means forvisualizing, for processing and for storing the data 13. As sensors 3,for example, epicordical electrodes, deep electrodes, brain electrodesor peripheral electrodes can, for example, be used.

The electrodes 2 each respectively has at least two wires at whose endsa potential difference is applied for the purpose of stimulation. Theelectrodes can also be microelectrodes or macroelectrodes.Alternatively, the electrodes each can comprise a single wire. In thiscase for the purpose of the stimulation, respective potentialdifferences are applied between the individual wire and the metallicpart of the housing of the generator. Additionally but not obligatory, apotential difference can be measured by means of the electrodes in orderto establish a pathological activity. In a further embodiment, theelectrodes 2 can each also be comprised of more than two individualwires which can serve both for the determination of measurement signalsin the brain as well as for the stimulation. For example, four wires canbe provided in a conductor cable, whereby between different ends apotential difference can be applied or can be measured. In this mannerthe magnitude of the area of the brain from which the signal is derivedas well as the area of the brain which is stimulated or the target areacan be varied. The number of wires from which the electrodes are made islimited as to its upper value only by the maximum thickness of the cablewhich is to be inserted into the brain so that the smallest amount ofbrain matter will be damaged. Commercial electrodes comprise four wires,although five, six, or more wires or only two wires may be comprised inthe electrode.

For the case in which the electrodes 2 each comprise more than twowires, at least two of these wires can also function as the sensors 3 sothat in this special case an embodiment is provided in which theelectrodes 2 and the sensors 3 can be united in a single component. Thewires of the electrodes 2 can have different lengths so that they canpenetrate to different depths in the brain. If the electrode 2 iscomprised of n wires, a stimulation can be effected over at least onepair of wires so that by the pair formation subcombinations of wires arepossible. Apart from this component additional sensors 3 can be providedwhich are not structurally united with the electrodes 2.

According to the invention, the device is provided with means which canrecognize the signals from the electrodes 2 or the sensors 3 aspathological and in the case of a pathological pattern, limit throughthe electrodes to stimuli which act upon the pathological neuronalactivity so that in the subpopulations of neurons which are stimulatedby the individual electrodes, a reset occurs and the neuronal activityof the entire population is desynchronized and the natural physiologicalactivity thus more closely approximated. The physiological activity fromthe healthy activity by a characteristic change in its patterns and/orits amplitude and/or its frequency count.

The means for reorganizing the pathological pattern can comprise acomputer which processes the electrical signals from the electrodes 2and/or the sensors 3 and compares the process signal with data stored inthe computer. The computer makes available through a data carrier thedata which is stored thereon. This can be enabled in the framework of acalibration and/or a control operation represented at 5.

The device according to the invention also comprises in one possibleembodiment, a unit 4 for signal processing and/or control or regulationof a computer and which includes a data carrier which carries the datarelating to pathological patrons and which can be compared with themeasured data. When reference is made herein to the data of thepathological patterns, parameters and measurement values which arerelevant for the stimulation are to be understood, for example, theinstantaneous frequency of feedback signals measured by the sensor 3,the thresholds required for demand or need controlled timing, thestimulation parameters which determine the stimulation amplitude likefor example the amplitude number of individual pulses of a highfrequency pulse train. All of the process-wise relevant parameters whichthe device of the invention requires to determine the type and strengthof the stimuli as well as the spacing in time thereof, and informationpertinent to the electrode-specific application of the stimuli which isrelevant for the demand controlled or need controlled function can bestored and derived based upon the measured values obtained from thesensor 3 or parameters derived therefrom. As a function of thedevelopment and expression of pathological features in the feedbacksignal in the embodiment described in section 4.3 hereof (below), thedemand or need controlled timing of a stimulus signal is outputted atthe electrodes 2 so that a stimulation of the brain tissue is effected.

The device of the invention, thus has means which is capable ofrecognizing the development and/or expression of the pathologicalfeatures in the feedback signal measured by sensor 3. The control unit 4is so programmed that for the timing of the embodiment described insection 4.3, the control unit 4 produces a stimulation signal which isoutputted at the electrodes 2. The control unit 4 can be thus programmedfor the periodic stimulation described in section 4.4 with a demand orneed stimulation amplitude, the control unit 4 will at specific,preferably periodically sequenced time points, generate a stimulationsignal with the amplitude calculated by the control unit 4 and deliverit to the electrodes 2. In a less preferred embodiment the controloperates without demand control or need control, that is without feedback control and generates as described in section 4.2, stimulationsignals which are delivered to the electrodes 2.

The control unit 4 can for example comprise a chip or another electronicdevice with comparable computing power.

The control unit 4 controls the electrodes 2 preferably in the followingways. The control data is reproduced by the control unit 4 to an opticaltransmitter 5 for the stimulation which, through the light conductor orwaveguide 6 controls the optical receiver 7 because of the opticalcoupling of the control signals to the optical receiver 7, a galvanicdecoupling of the stimulation control of the electrodes 2 is effected.This means that the effect of noise signals from the signal processingunit and control 4 into the electrodes 2 can be prevented. As theoptical receiver 7, for example, a photocell can be considered. Theoptical receiver 7 transmits the stimulation signals received via theoptical transmitter 5 for stimulation, to a stimulator unit 8. Via thestimulator unit 8, the targeted stimuli are applied through theelectrodes 2 to the target region of the brain. For the case in whichmeasurements are also to be made be the electrodes 2, apart from theoptical stimulation transmitter 5, a relay 9 is also connected to theoptical sensor which prevents the incursion of noise signals. The relay9 or an equivalent transistor ensures that the neuron of activity can bemeasured again directly after each stimulus without overriding theisolating amplifier. The galvanic decoupling does not necessarilyrequire an optical coupling of the control signals. Rather otheralternative control systems can be provided. These can for exampleinvolve acoustic coupling, for example in an ultrasonic range. A noisefree control can also for example be realized with the aid ofappropriate analog or digital filters.

Furthermore, the device according to the invention is preferablyprovided with means for visualizing (displaying) and processing thesignals as well as for data security 13 utilizing a telemetry Receiver12. The unit 13 can be provided for the data analysis in the methoddescribed below.

In addition, the device according to the invention, using the telemetryreceiver 13 can be connected to an additional reference data base toassist for example in the monitoring of the device and for carrying outthe control mechanisms described in sections 5.1.2 hereof for efficientmodification of the parameters. For example, as described in section5.1.2.2.2 (below), the minimum number of individual pulses of the highfrequency pulse train can be raised or lowered in order to increase orreduce the strength of the desynchronizing effect of the stimulation.

In FIGS. 2 a and 2 b, the abscissas give the time axis in seconds whilethe ordinates display the amplitude of the local field potential (FIG. 2e) or the neuronal discharge pattern (FIG. 2 b) each in optional units.The amplitude of the local field potential (FIG. 2 a) measured by sensor3, service as the feed back signal for the need controlled or demandcontrolled timing. whenever a threshold of the feedback signal isreached the next stimulation with the same excitation pulse is effected.The vertical lines symbolize the beginning and end of the appliedexcitation pulses of four electrodes 2. The latter have been shown inFIGS. 4 a through 4 d and comprise two time-offset pairs of highfrequency pulse trains each pair is comprised of two high frequencypulse trains of different polarities. The bars between the verticallines in FIGS. 2 a and 2 b symbolize the both airs of high frequencypulse trains:

The upper bar corresponds to the pair illustrated in FIGS. 4 a and 4 b,the lower bar belongs to the pair in FIGS. 4 c and 4 d.

FIGS. 3 a and 3 b indicate the time axis along the abscissa in secondswhile along the ordinates the amplitude of the local field potential(FIG. 3 a) and the neuronal discharge pattern (FIG. 3 b) are given inoptional units.

The amplitude of the measured local field potential from sensor 3 (FIG.3 a) serves as the feedback signal for the periodic application of thestimulus with demand- or need control stimulation amplitude. The highfrequency pulse trains shown in FIGS. 4 a to 4 d are periodicallyapplied, whereby within one of the total stimuli applied via the fourelectrodes 2 the lengths of all four high frequency pulse trains isidentical and matches the measured local field potential prior to thestimulus application. The vertical lines symbolize the beginning and endof the stimulus applied by the four electrodes 2. The latter have beenshown in FIGS. 4 a through 4 d and are comprised of two time-offsetpairs of high frequency pulse trains. Each pair is comprised of two highfrequency pulse trains of different particularity. The bars between thevertical lines in FIGS. 3 a and 3 b symbolize the two pairs of highfrequency pulse trains: The upper bar corresponds to the pair shown inFIGS. 4 a, 4 b, the lower bar belongs to the pair shown in FIGS. 4 c and4 d. The demand controlled selected lengths of the high frequency pulsetrains are symbolized by the lengths of the upper and lower bars inFIGS. 3 a, 3 b.

In FIGS. 4 a through 4 d the abscissas of the time axes are given inseconds while the ordinates are shown in optional units to indicate thestrengths of the individual pulses for example in the sense of theapplied currents. For better visualization, the individual pulses havebeen filled in in black. Over the first two electrodes 2 the same highfrequency pulse trains but with different polarities are applied (FIGS.4 a, 4 b). The same pair of high frequency pulse trains but with a timedelay are applied to a third and fourth applied electrodes.

In FIGS. 5 a through 5 d the abscissas are the time axes in secondswhile the ordinates show the strength of the individual pulse, forexample, in the sense of the applied current in arbitrary units. Forbetter visualization the individual pulses have been filled in in black.

By means of the first two electrodes to the same high frequency pulsetrain with the same polarities are applied (FIGS. 5 a, 5 b) the samepair of high frequency pulse trains in a time delayed manner are appliedby means of the third and fourth electrodes (FIGS. 5 c and 5 d).

Below the device of the invention and its functioning will be describedin greater detail by way of example.

The device of the invention and its control are equipped with means toenable all steps of the method of the invention to be carried out. Withthe disclosed method steps, therefore, the means for carrying them outwith the device is implicitly disclosed as well. The method stepspresent simultaneously are functionalized description of the features ofthe device.

According to the invention, the electrodes are introduced into the brainregion which is answerable for the formation of the pathologicalpattern. At least two, preferably four, or even three or more electrodesare introduced according to the invention either directly in the regionor in one or more regions connected with the region having the nervecell populations or nerve fiber bundles which are responsible for thepathological pattern. The number of electrodes is only limited in thatno optionally high density of electrodes can be provided in any singlebrain region without unnecessarily damaging the tissue and introducing arisk of bleeding in the implantation of the electrodes. In any case, thenumber of electrodes in the region can be N where N is greater than orequal to 2. Each electrode thus outputs in its vicinity a signal whichis effective either directly in its surroundings or is conducted by anerve fiber bundle into another area in which it can bring about aresetting of the neurological activity. The electrode signals which cangive rise to a reset are already known to the skilled worker in the art:

It can for example be an individual pulse or high frequency pulse trainwith a pulse rate greater than 100 Hz. The device of the inventionenables, via its control the selection of which of the at least twoelectrodes 2 will effect the reset either in its immediate environmentand/or by conduction of the stimulation through a fiber bundle toanother brain area.

According to the invention, N electrodes, where N is greater than orequal to 2, are so controlled that a phase shift in time of theindividual electrode signals by T/N is provided to the extent that thestimulating electrodes 2 are to be found in the area to bedesynchronized. T is, as is described below, the period of the rhythmicactivity to be desynchronized. In case at least one of the stimulatingelectrodes 2 are not located in the area to be desynchronized, in thecontrol of such an electrode 2 the transit time between the location ofthe stimulation and the location of the neuron population to be effectedby the stimulus is taken into consideration. This is described insection 5.2 below. The device of the invention has a control which inthe case of N electrodes is able to stimulate them for substantiallyeach a Nth of the period of the activity to be desynchronized with thetime shifted reset signal. The phase shifting in time can beadvantageously substantially equidistant. By the phase shifting weunderstand the difference between the phases of the rhythmic activity tobe desynchronized as influenced by the different electrodes 2.Surprisingly, with this equidistant phase shifted reset by the Nelectrodes 2 acting upon the neuron populations respectively affected bythem, a desynchronization of the entire neuron population to bedesynchronized can be effected together with a suppression of thepathological symptoms. If at least one electrode 2 is outside the areato be desynchronized, the effect of indirect stimulation must beconsidered as has been described in section 3.2 hereof. This isdeveloped in greater detail in sections 3.3, 3.4 and 5 hereof.

With the new method and the new device, the desynchronization is carriedout qualitatively differently from that of the above described state ofthe art. Instead of applying signals synchronously to a pathologicallyeffected nerve cell group in a vulnerable phase of its rhythm, the nervecell group is simply with time coordination stimulated at a number oflocations in a manner which causes the desynchronization to arise. Forthis purpose at the individual stimulation locations either electrical,individual or single pulses can be used or a low frequency stimulationsequence or a high frequency stimulation sequence can be used. It isessential that at least two and preferably more than two stimulationlocations be stimulated. If N stimulation locations are stimulated theentire nerve cell population to be desynchronized is subdivided intosubstantially N equidistant subpopulations (in the phase cycle). Thatmean that the phases of the neuronal activity of the subpopulationsfollow one another in substantially equidistant steps of 2π/N, 2π is thelength of a period which has also bee defined above as the phase cycle.This utilizes the fact that the pathologically increased interactionbetween the neurons can contribute to the desynchronization. In thiscase one utilizes the surprising presence of a self organization processof the neuronal population which is answerable for the pathologicalsynchronization to assist in eliminating it. The same applies where thesubdivision of the subpopulations is on an equidistant basis, that isthat the subdivision of the total population into subpopulations iseffected so that the phases therein will be equidistant and adesynchronization will be accomplished. In contrast thereto, without apathologically increased interaction, no desynchronization will beeffected. The energy of the system itself is thereby utilized to producea therapeutic effect an equidistant division into subpopulations is muchmore easily brought bout in a complete desynchronization as with thedescribed methods as the state of the art. The best results are obtainedwhen an equidistant phase shift or a substantially equidistant phaseshift of the phase resetting stimuli is applied. From a treatment pointof view it is of greater advantage still when the stimulating pulsesoutputted by the electrodes have the phases of the stimulatedsubpopulations at least partially shifted relative to one other. Thetreatment results are better as the phase shift produced approaches anequidistant phase shifting.

1. Mechanism of the Stimulation:

The goal of the stimulation is to counteract a pathologically createdsynchronization in a nerve cell population by desynchronization. Forthis purpose, the nerve cell population to be desynchronized is soinfluenced at at least two locations by the phase shifted stimulation atdifferent places in the brain that primary at least two subpopulationsof the total nerve cell population are formed. Because of thepathologically created interaction between the nerve cells the statecreated by the stimulation is unstable in at least these twosubpopulations and the entire nerve cell population have quicklyapproaches a state of complete desynchronization. The desired state,that is the complete desynchronization is thus not present immediatelyafter the application of a stimulation but typically develops over ashort period, usually not less than one period of the pathologicalresponse. With the desynchronization methods described in the prior art,the nerve cell population to be desynchronized is directly brought intoa desynchronized state. This however only occurs by an adequateselection of the stimulation parameters whereby these must be preciselycalibrated and can only have limited tolerances.

The device according to the invention by contrast stimulates the nervecell population to be desynchronized in a qualitatively differentmanner: by the coordinated timed stimulation of subpopulations, thenerve cell population to be desynchronized is split into at least twosubpopulations. This process functions for a greater range of thestimulation parameters and requires no expensive calibration and caninvolve much larger tolerances. The reasons for this is that unlike thestate of the art described previously, the invention does not requirethe presence of a vulnerable phase which can make up only about 5% of aperiod of the rhythm to be desynchronized. Rather the stimulationoperates independently from the dynamic starting state.

2. Type of the Individual Stimulation:

As an individual stimulus or single pulse, a stimulus is intended whichcan be applied by a single electrode 2 in contrast with a singlestimulus reference may be made herein below to a single pulse whereasthe single stimulus may be an individual pulse shaped monophasic orbiphasic stimulus.

A single pulse can either be a single stimulus or part of a highfrequency or low frequency pulse train. For a stimulation which iscoordinated in time over at least two electrodes, individual stimulusesare used which are recognized by the skilled worker in the art as forexample:

a) electrical monophasic or biphasic single pulses;

b) electrical high frequency pulse trains with a pulse rate ofpreferably more than 100 Hz, whereby the single stimulus of the pulsetrain can be monophasic or biphasic individual pulses;

c) electrical low frequency pulse trains whereby with a pulse rate f inthe order of magnitude of the frequency g of the rhythm to bedesynchronized, monophasic or biphasic individual pulses or a brief highfrequency pulse train can be applied of less than preferably one totwenty monophasic or biphasic individual pulses. In this case thefrequency of the pulse rate of the low frequency train is givenadvantageously substantially by the ratio f/g=n/m, whereby n and m aresmall whole numbers preferably 1, 2 or 3;

d) apart from the substantially periodic sequences of individual pulsesin a high frequency pulse train or low frequency pulse train given in b)and c) above, the point in time of the application of the individualpulses in a pulse train can also vary stochastically [randomly] and/ordeterministically.

Under “coordinated stimulation with time” a condition will be understoodin which the individual stimuli are applied to the respective electrodes2 at respective points in time, which possibly are different from oneanother, as described in Section 4.1 (below) in order to produce betweenthe stimulated subpopulations the phase difference with the therapeuticeffect for the neuron population to be desynchronized. The device isthus provided with means which can apply the described electricalmonophasic and/or biphasic individual pulses and/or electrical highfrequency pulse train and/or electrical low frequency pulse train of thedescribed types. The means are the electrodes 2 and the control 4 whichoutputs control signals to the electrodes 2 for triggering thesestimuli.

As the total stimulus, the individual stimuli applied via the electrodes2 are intended which, according to the mechanism by which the device ofthe invention operates, evokes a desynchronization in the neuronpopulation to be desynchronized. Examples of total stimulus are shown inFIGS. 4 a through 4 d and FIGS. 5 a through 5 d. In the framework of atotal stimulus, preferably a single stimulus is delivered by eachelectrode.

With repetitive applications of the total stimulus, the electrodes 2which are effective in the framework of the total stimulus can bevaried. Especially a part of the electrodes 2 which receives therespective total stimulus can be controlled or varied based upon theselection made with a stochastic [random] and/or deterministicalgorithm.

3. Number and Spatial Arrangement of the Electrodes

3.1 Number of Electrodes:

The number of electrodes used is a compromise of 2 contrary requirementsor desiderata:

On the one hand the neuron population to be desynchronized by thestimulus should be divided into the greatest number of functionalsubpopulations as possible. This can be achieved by providing as meanselectrodes as possible for the stimulation. On the other hand, thenumber of electrodes to be implanted should be held as small as possiblein order to avoid unnecessary tissue damage and above all to avoidbleeding in the brain during the implantation. For example, at least twoelectrodes are used. Three electrodes can also be used. Especiallypreferred is the use of four electrodes since the desynchronization withfour electrodes is more pronounced and lasts longer. With the increasein the number of electrodes to, for example, at least two electrodes areused. Three electrodes can also be used. Especially preferred is the useof four electrodes since the desynchronization with four electrodes ismore pronounced and lasts longer. With the increase in the number ofelectrodes to, for example, 5, 6, 7, 8, 9 up to 100 or more, thedesynchronization effect becomes more pronounced and the duration isimproved. The use of a large number of electrodes, for example, 100electrodes can only be realized with microelectrodes and modernneurochip technology.

3.2 Definition of the Concept:

In the following, by the term “target population” the nerve cellpopulation which will be stimulated directed by an implanted electrodewill be understood.

A target population is thus directly stimulated by an electrodeimplanted at all or nearby.

The nerve cell population which is pathologically synchronously activeis indicated as the area to be desynchronized or as the nerve cellpopulation to be desynchronized. The latter is not anatomically bounded;rather it can include at least one component from the following group:

at least a part of at least one anatomic area, or

at least one complete atomic area.

The area to be desynchronized can be either directly or indirectlystimulated.

Direct stimulation by a stimulation electrode 2:

In this case, the stimulation electrode 2 is located in the area to bedesynchronized. This electrode 2 effects thereby the target populationwhich is found in the area to be desynchronized.

Indirect stimulation by a stimulation electrode 2:

In this case the area to be desynchronized is not directly stimulated bymeans of electrode 2. Rather a target population or a fiber bundle,stimulated by the stimulation electrode 2 is functionally tightlyconnected with the area to be desynchronized and delivers thedesynchronizing stimulus thereto. In this case, the stimulation effectis communicated to the area to be desynchronized preferably by ananatomical connection. For the indirect stimulation, the term targetarea will thus refer to the target area population and the communicatingfiber bundle. The term target area in the following will be understoodto mean the area to be desynchronized and the neuron populationsfunctionally tightly connected thereto and any connecting fiber bundle.

The stimulation mechanism according to the invention is intended tostimulate the neuron population to be desynchronized by the individualelectrodes at given, typically different points in time within a periodof the oscillating activity of, that neuron population. The time spacingbetween individual stimuli are fractions of the period of theoscillating activity to be desynchronized and amount preferably tosubstantially a Nth of the period where N is a small whole number, forexample, 4. N is thus a whole number which is preferably below 1000,even more preferably less than 100 and especially can be less than 10.The period of the oscillating activity to be desynchronized which servesas the time reference for the application of the individual stimuli isdesignated as the stimulation period T. The term stimulation T is thuscentral for the functioning of the invention as is set out in section5.1.2.2.2 (below) describing the process following the stimulated periodT which is neither adjusted by calibration nor by measurement during thestimulation operation but rather is imposed by the neuron population tobe desynchronized.

Under the term “rhythm” will be understood the rhythmic and thusapproximately periodic neuronal activity which amounts to a pathologicalsuperimposition of synchronous activity on the nerve cells. A rhythm canlast a long time or appear only briefly. A reset of a neuron populationwill be understood to mean the reset or restoration of the phaserelationships of the natural activity of this neuron population.

3.3 Embodiment for the Case in which all Electrodes are Positioned inthe Nerve Cell Population to be Desynchronized:

The N electrodes should preferably be so arranged that with eachindividual electrode a Nth of the nerve cell population to bedesynchronized is directly stimulated. This can be realized withdifferent numbers of electrodes and different geometrical arrangementsof the electrodes with respect to one another. For example, an optionalunsymmetrical arrangement can be selected. Preferred, however, is asubstantially symmetrical arrangement since in this case thestimulation, directed functional division into subpopulations enablesthe smallest current input to be experienced. For example, the endpoints of the electrodes projected among the electrodes can give asquare. For example, six electrodes can also be used. In that case, fourare preferably arranged in a square pattern in one plane while the othertwo substantially equidistantly perpendicular to this plane whereby itsconnection lie forms substantially a rotation axis for the fourelectrodes arranged in a square. For the greatest effect in variousgeometric arrangements the electrodes at least partly can have differentlengths.

3.4 Embodiment for the Case that at Least One of the Electrodes is notPositioned in the Nerve Cell Population to be Desynchronized.

In this stimulation configuration, at least one target area differentfrom the area to be desynchronized is stimulated. As has been describedin section 3.2 above, the indirect stimulation is communicated to thenerve cell population to be desynchronized from the various neuronpopulations and/or the stimulation of the nerve cell population to bedesynchronization is carried out by the fiber bundles connectedtherewith.

Thus in a target area or in the area to be desynchronized either atleast one electrode or a multielectrode arrangement in the sensedescribed in section 3.3 above can be used.

4. Demand Controlled or Need Controlled Application:

4.1 Pattern and Polarity of the Stimulus:

In the framework of the application of a stimulus, through eachindividual electrode 2 an individual stimulus is applied. The individualstimuli can have the forms described in section 2 hereof above.

The individual stimuli applied via the various electrodes 2 can howeveralthough they need not, differ in type and/or energy input. For thispurpose, the device according to the invention is capable, with respectto its control, to be so programmed that it can vary the type and/or theenergy input of the individual stimuli.

The individual stimuli applied through an individual elected in therepeated application of the stimulus need not however have its typeand/or energy input varied. For example, in the case of a directstimulation with N electrodes, each can have the same individualstimulus applied with a time delay of respective T/N whereby T is thestimulation. For example, N=4 the time spacing of the individual stimuliwill follow at T/4 after one another over the first, second, third,fourth electrode 2 as illustrated in FIGS. 5 a to 5 d. For this purpose,the device of the invention has a control which is so programmable thatthe N electrodes 2 are triggered with a time delay of substantially T/Nfor individual stimulus application.

Alternatively, thereto, for example with the demand control timingdescribed in section 4.1 above, especially, the sequence of theindividual stimuli can be controlled systematically within the totalstimulation or randomly that is in accordance with a deterministic orstochastic law. For this purpose, the device according to the inventionis equipped via its control which can be so programmed, that it controlsthe sequence of the individual stimuli can be controlled systematicallywithin the total stimulation or randomly that is in accordance with adeterministic or stochastic law. For this purpose, the device accordingto the invention is equipped via its control which can be so programmed,that it controls the sequence of the individual stimuli within a totalstimulus deterministically and/or stochastically.

By varying the sequence of the individual stimuli within the totalstimulus, adaptation processes in the neuron population which haverequired increases in the stimulation intensity to reach the sametherapeutic effect over time, are bypassed.

As a further additional possibility, time delays in the stimulusapplication can be replaced by alternations of the polarity of theindividual stimuli. For this purpose, the device of the invention isequipped, through its control which can be so programmed, that it cancontrol at least one of the electrodes 2 so that alternating polaritiesare applied thereto. For example, is N=4 over the first and secondelectrodes two and after a time delay of T/4, over the third and fourthelectrodes 2 respectively a pair of monophasic or biphasic individualpulses of opposite polarities can be applied as has been illustrated inFIGS. 4 a to 4 d for the monophasic individual pulses.

4.2 Non-Demand Controlled Stimulus Application.

The total stimulation described under section 4.1 hereof can be appliedin a simpler embodiment without demand control. In this case, the totalstimulation can be strictly periodic in time or nonperiodic in time. Inthis embodiment, the device according to the invention is equipped, overits control, and so programmed that it does not enable demand controlledapplication of the total stimulus. The total is then so programmed thatit is capable of outputting the total stimulus periodically and/ornonperiodically. A nonperiodic sequence in time of the total stimuluscan be generated in a stochastic process.

4.3 Demand Controlled Timing:

Under the “timing”, the timing pattern of the stimulus application ismeant.

With sensor 3, the feedback signal resulting from the activity of theneuron population to be desynchronized is measured. This feedback signalis fed back to the unit 4 for processing and regulation 9 the means forrecognizing a pathological feature of characteristic. As soon as theunit 4 for signal processing and/or regulation recognizes thepathological signal, a stimulus is applied. By a pathological feature,should be understood, for example, one or more of the followingcharacteristics of the feed back signal:

(a) The amplitude of the feedback signal exceeding a threshold value.The device of the invention is thus in a preferred embodiment equippedwith means for recognizing aa threshold value of the feedback signal. Inthis case, preferably the feedback signal itself or its magnitude or anamplitude can be compared with the threshold value. The means forrecognizing the threshold value can in this embodiment be so programmedthat it compares the feedback signal there is and/or a value of atand/or an amplitude thereof with the threshold value. To determine theamplitude, in a simple version one can determine the value of the signalor utilizing band pass filtration and a subsequent Hilberttransformation for wavelet analysis. The unit 4 for signal processingand/or regulation is so programmed in this case that it can determinethe magnitude of the signal and/or the result of a bandpass filteringand carry out a Hilbert transformation or a wavelet analysis.

The feedback signal or its magnitude are used especially preferablysince the calculation of the amplitude requires a significantly higherexpenditure of computing resources and the precision of this calculationdepends upon the correct choice of the algorithm parameter.

In addition, the determination of the amplitude cannot be carried out ona single measurement value of the feedback signal but must be carriedout at sufficiently large time intervals within the skill of the workerin the art.

Through this type of analysis of the feedback signal in a slidingwindow, the recognition of the pathological feature is somewhat delayed.The form of analysis described in part (a) hereof of the shape of thefeedback signal is to be used when the pathological activity to bedesynchronized is exclusively measured by the sensor 3 or predominantlymeasured by the sensor 3.

(b) In case the sensor 3, in addition to this activity additionallymeasures non illness specific activity;

for example, from other neuron populations, in the analysis of thefeedback signal a further algorithmic step must be introduced.

Since the illness-specific activity typically arises in a frequencyrange which is different from the frequency range of the nonillnessspecific activity it suffices advantageously to estimate the activity inthe illness specific frequency range. The frequency of the illnessspecific activity is for example determined from the time differencefrom the trigger points which arise in succession. Trigger points arecharacteristic points, like maxima, minima, inflection points and zeropassages.

Preferably this analysis is carried out in a sliding time window wherebythe mean value of a multiplicity of time differences are formed, therebyincreasing the stability of the frequency estimation. Alternatively, thefrequency estimation can also be made by the known spectral estimationmethod and other frequency estimation techniques within the skill andknowledge of the worker in the art.

For this purpose the device of the invention in a special embodiment,comprises means for estimating the activity in the illness specificfrequency range, for example, by the spectral estimation method, bywavelet analysis. This can for example be achieved with a frequencyanalysis by the means for carrying out the frequency analysis. Forexample the spectral energy in the illness specific frequency range canbe determined in a sliding window. Alternatively, after band passfiltering the amplitude in the illness specific frequency range can bedetermined by first determining the maximum of the band pass filter,signal or the mean value of the magnitude of the band pass filter, orusing subsequent Hilbert transformation or wavelet analysis. For thispurpose the device according to the invention comprises for example,means for carrying out a band pass formation of the amplitude and meansfor determining the maximum of the band pass filter system and, formeans for determining the mean value of the band pass filter signaland/or means for carrying out a Hilbert transformation and/or a waveletanalysis.

In the case of demand controlled timing, for example, always the samestimulus will be used. Preferably the stimulation period, as will bedescribed in section 5.1.2.1 hereof above, will be matched to theinstantaneous frequency of the neuron population to be desynchronized.To that population a stimulus is applied upon the existence of thepathological feature over the stimulation period and which is matched tothe instantaneous frequency. The intensity of this stimulus remainspreferably constant. Preferably the intensity is modified as describedin section 5.1.2.2.1 hereof above, in accordance with the stimulationeffect.

4.4 Recurrent Stimulation in Demand Controlled Stimulation Strength:

The feed back signal is measured by the sensor 3 and indicates theactivity of the neuron population to be desynchronized. This feedbacksignal is fed to the unit 4 for signal processing and/or regulation. Thesignal processing and/or regulating unit 4 produces a recurrent,preferably periodic stimulation whose strength of the stimulus appliedat each respective point in time dependent upon the expression of thepathological feature in the feedback signal. For this purpose, theintensity or the duration or—when pulse trains are used—the number ofindividual pulses of the pulse train is matched to the expression of thepathological feature. In a time window of freely selectable andpreferably constant length, which ends at a constant time spacing beforethe respective stimulus, the expression or the pathological feature isdetermined in the following way:

(a) In the case in which a sensor 3 exclusively or predominantlymeasures the pathological activity to be desynchronized the amplitude ofthe expression of the synchronization in the neuron population to bedesynchronized corresponds to the measurement. The amplitude thusrepresents the pathological feature. The amplitude can be estimated froma determination of the maximum of the signal or using the mean value ofthe magnitude of the signal or with band pass filtration with subsequentHilbert transmission or wavelength analysis.

The first two variants (determining the maximum of the signal ordetermining the mean value of the signal) are used especially preferablysince the calculation of the amplitude by means of a Hilberttransformation wavelet analysis requires a significantly higherexpenditure of computer resources and the precision dependent upon thecorrect choice of the algorithm parameters.

(b) In case the sensor 3 measures, apart from the illness specificactivity additionally also nonillness specific activity, from anotherneuron population, for the estimation of the expression of thepathological feature the feedback signal cannot directly be used. Sincethe illness specific activity typically arises in a frequency rangedifferent from the frequency range of the known illness specificactivity the estimation of the activity of the illness specific range iscarried out in this case. This can be achieved for example by afrequency analysis. For example the spectral illness in the illnessspecific range can be determined. Alternatively after band passfiltration the amplitude can be determined by measuring the maximum ofthe band pass filtered signal or the average value of the magnitude ofthe signal or after a subsequent Hilbert transformation or by waveletanalysis.

4.5 Establishing the Demand or Need:

On at least two grounds, there is no stronger relationship between theexpression of the pathological feature and the expression of the illnessspecific symptom. Firstly, there is a spacing of the sensor 3 from thearea in which the feedback signal should be generated and which effectsthe amplitude in the illness frequency range. Secondly, for a certainexpression of the illness specific feature, that is the expression ofthe rhythmic activity in the illness specific frequency range, is notsingular with the illness specific symptom. Since the illness specificrhythm acts on and through over complex nerves complex in the brain thedynamic relationship is not a linear one and thus there is no fixedrelationship between the pathological rhythm and the expression of thesymptom. When for example the pathological rhythm does not sufficientlycoincide with the biomechanically given intrinsic frequency of anextremity, the tremor produced by the pathological rhythm issufficiently the case when the pathological rhythm is in resonance withthe biomechanically determined intrinsic frequency of the extremity.

The measurement for a given location of the sensor 3 provides a feedbacksignal which will be understood by the skilled worker to like within anexperience range. The value of the expression and the feedback signalmeasured by the sensor 3 as to the pathological feature, when it exceedsthe threshold typically representing the development of symptoms fortremors is used. The threshold is a parameter which is utilized in theembodiment described in section 4.3 as the basis for the need controlledtime. The device of the invention thus includes means for detecting orprovide a threshold value. With the need control timing the advance isgained that the effectiveness does not depend critically upon theselection. Rather the threshold changes can be made with largetolerances which can be upped to 50% of the maximum expression of theillness specific feature.

The choice of the threshold can either be intraoperative or made in thefirst days after the operation by measurement of the signal over thesensor 3 and determination of and monitoring of the expression of theillness specific feature and its comparison with the expression of thesymptom for example the degree of shaking or tremor.

In a further preferred embodiment, as the threshold representative valueis selected, for example, the mean value of thresholds of patients overa collection of patients.

In the embodiment described in section 4.4 the recurrent stimulationwith need controlled stimulation strength, no threshold is necessary.

5. Calibration and Regulation.

5.1 All Electrodes 2 Lie in the Neuron Population to be Desynchronized.

5.1.1 Stimulation Parameter for the Beginning of Stimulation:

5.1.1.1 frequency selection of the frequency without prior operation ofthe device: The frequency range of the pathologically neuronal activityis known for respective pathological images by the skilled worker in theart (Elble R. J. and Koller E. C. (1990): Tremor John Hopkins UniversityPress, Baltimore). From this frequency range, preferably the averagevalue can be taken. Alternatively, instead of this average value, from adatabase, the frequency can be chosen which is the expected value basedupon the age and the specific disorder and its severity.

It is not necessary for the effective operation of the device accordingto the invention that the frequency given at the outset coincide withthe actual frequency of the neuron population to be desynchronized. Theregulation which is described under 5.1.2.1 hereinafter of thestimulation period T functions also when the correct frequency valuedeviates greatly from the starting value. The reference to a strongdeviation includes a value which may be by a factor of at least 10 foldtoo large or too small. Alternatively one can begin with a frequencyvalue known to the worker in the art which is a typical frequency rangefor the illness.

Selection of the frequency with prior operation of the device: As thestarting value for the frequency the mean value or average of thefrequency during the previous operation of the device is selected inboth cases that with and without previous operation of the device thestimulation period T is calculated as the inverse of the starting valueof the frequency.

5.1.1.2 Intensity:

5.1.1.2.1 Demand-Controlled Timing:

The starting value of the stimulation parameter which determines theintensity of the individual stimulation for example length of the highfrequency pulse train, an amplitude and duration of the individual pulseand pause for interval between individual pulses. Of the individualpulse of 60 to 200 μs, a rate of the individual pulses of 120 Hz, anamplitude of 4 volts. The starting values for the frequency andintensity can be thus previously given and need not be determined,especially using time consuming calibration.

5.1.1.2.2 Recurrent Application with Need Controlled Stimulus Strength.

The starting values of the stimulation parameter which determines theintensity of the maximum stimulus (length of the high frequency pulsetrain, amplitude and duration of the individual pulses and intervalbetween individual pulses) are selected by the artisan based upon knownexperiential ranges (for example, a high frequency pulse train with twoindividual pulses, individual pulse duration of 60 to 200 μs, rate ofindividual pulses 120 Hz amplitude 4 volts).

The starting value of stimulation parameter which determines theintensity of the minimum stimulus (for example length of high frequencypulse train amplitude and duration of the individual pulses and intervalbetween pulses) is determined by the artisan experientially, (forexample a high frequency pulse train with three individual pulses,individual pulse duration of 0 to 200 μs, rate of the individual pulses120 Hz V volts).

5.1.2 Regulating Mechanism of the Device According to the Invention orits Control During the Stimulation.

5.1.2.1 Matching the stimulation period T: in the target area or an areaclosure connected therewith, the feedback signal is measured. Forexample in Parkinson instead of a measurement by the stimulationelectrodes, a measurement can be carried out of the activity in theadjacent area, for example, the promoter cortex, using epicordicalelectrodes. In a time window with the length given below, the dominantmean frequency is determined. For this purpose different algorithms canbe used. For example the frequency can be determined as the inverse ofthe instantaneous period whereby the instantaneous period is obtainedfrom the time difference between maximum of the feedback signal whichfollow one another. In case the sensor 3 does not measure only illnessspecific activity, for this type of frequency estimation the illnessspecific activity must be first extracted by a band pass filter for theillness specific frequency range. Alternatively, for example thefrequency can be estimated by the technique described in section 4.3hereof. The stimulation period T is taken as the inverse of the meanfrequency.

The time window for this frequency estimation which can be open towardthe upper values, can be for example ten thousand periods, preferablyone thousand periods, and especially preferably one hundred periods ofthe illness activity or also some other optional value.

5.1.2.2 Demand or Need Control

5.1.2.2.1 Demand or need controlled timer. When the feedback signalexceeds the threshold values the respective next stimulation is effectedpreferably with the same stimulus. For this purpose the device isprovided with a control which after detecting a crossing of thethreshold value outputs a stimulating signal to the electrode 2. If thedesired effect is not obtained, that is that the target population isnot sufficiently disclosed and the feedback signal does not fall backbelow the threshold value, the strength of the stimulus is raised to amaximum value that is selected based on safety, for example in steps of0.5 volt per 50 periods.

For this purpose the device of the invention is provided with a controlwhich can recognize the change in the feedback signal and in the absenceof a change in the feedback signal will match the stimulating signalvalues as described previously. After for example 20 stimuli, the devicecan begin to slowly vary the setpoint value (for example in steps of 0.5volt per 200 periods) to raise it as long as the simulation iseffective. The stimulation effect can be determined as in section 4.5hereof. The control is thus so programmed that it recognizes the changein the feedback signal and thus the stimulation effect.

5.1.2.2.2 Repeated Application with Demand Controlled or Need ControlledStimulation Strength:

5.1.2.2.2.1 Rapid Control:

The time interval between the individual stimuli are substantially wholenumber multiples of the stimulation period T. That means that the timeinterval between the beginning or preferably the end of the applicationbetween stimuli following one another is given by

t _(j+1) −t _(j) N _(j) T  Formula 1

In Formula 1, t_(j) is the time point of the beginning or preferably theend of the j^(th) stimulus. T is the stimulation period and N_(j) is awhole number. The time period given by t_(j+1)−t_(j) must not, asdefined in Formula 1, strictly correspond to a whole number multiple ofT but can also be given in accordance with

t _(j+1) −t _(j) =N _(j) T+x _(j)  Formula 2

whereby x_(j) is small by comparison to the stimulation period T. Thedevice according to the invention comprises, in one embodiment, acontrol which preferably outputs the stimuli to the electrodes 2 in timeframes or time compartments which are substantially whole numbermultiples or integral multiples of the stimulation period T. Basicallyall imaginable variations of time intervals are possible but asubstantially strictly periodic application of the stimuli is preferred.That means it is preferable to provide a constant number sequence likefor example N₁, N₂, N₃, where N_(j)=N for all j=1, 2, 3 etc. With anumber sequence like N₁, N₂, N₃, etc, a constant number sequence can bedeviated from for example by the use of a periodic, quasiperiodic,chaotic or stochastic [random] programming.

The strength of the individual stimulus is matched by the control of theinvention to the expression of the pathological feature in the feed backsignal for example in the following way:

In a time window before the application of the stimulus, the expressionof the pathological feature of the feed back signal is estimated as inSection 4.4 hereof above. For that purpose, for example, the amplitudeof the oscillating activity in the pathology specific frequency range isdetermined by an averaging of the magnitude of the corresponding bandpath filter feed back signal in a time window prior to the stimulusapplication. The strength of the stimulus used is determined by theexpression of the pathological feature as described in Section 4.4. Asthe pathological feature is expressed more strongly so the appliedstimulus will be stronger. The control according to the invention isthus so programmed in this embodiment that it increases the energy inputand the strength of the stimulus signal at the electrode 2 with theincreasing magnitude of the feed back signal. The relationship betweenthe expression of the pathological feature and the stimulus strength canin the simplest case be linear, although it can also have a complexform, for example a nonlinear form. The stimulus strength can be variedby varying different stimulation parameters like the number ofindividual pulses in high frequency pulse train or low frequency pulsetrain or the amplitude of the individual pulses for the duration of theindividual pulses. Preferably the number of individual pulses in thehigh frequency pulse train will be varied.

The number of individual pulses in the high frequency pulse train whichare applied to the k^(th) electrode 2 in the frame work of the j^(th)total stimulation is indicated as M_(j) ^((k)) can be carried outseparately for the individual electrodes 2. Preferably however thematching is carried out for all of the electrodes 2 in the same manner.That means that M_(j) ^((k))=M_(j) ^((l)) for k,l=1, 2, 3, . . . , Nwhereby N is the number of electrodes 2. In this case the number of theindividual pulses of the high frequency pulse train is given byM_(j)=M_(j) ^((k)) for k=1, 2, 3, . . . , N. The device of the inventionis thus so programmed that it can vary the stimulation strength in theindicated manner.

As has been described in Section 4.4 above, the expression of thepathological feature, for example, as the amplitude of the oscillatingactivity in the pathologically specific frequency band, is determined.For this purpose, for example in a time window before the application ofthe j^(th) stimulus, the magnitude of the illness specific frequencyrange band path filter signal is determined. The value determined inthis matter is indicated as A_(j).

The relationship between the number of individual pulses in the highfrequency pulse train M_(j) and the amplitude A_(j) can be given, by wayof example, by

$\begin{matrix}{M_{j} = {{A_{j}\frac{M^{{ma}\; x}}{A^{{ma}\; x}}} + M^{m\; i\; n}}} & {{Formula}\mspace{14mu} 3}\end{matrix}$

whereby M^(min) is the minimum number of the individual pulses in thehigh frequency pulse train.

The quotient M^(max)/A^(max) is apart from M^(min) the second parameterwhich is set. M^(max) and A^(max) are values which are within theexperience of the skilled worker in the art and allow the definition ofthe quotient M^(max)/A^(max)=C. Formula 3 determines the rapid controlfor each stimulus, providing the requisite stimulus strength, in thiscase through the number of individual pulses of the high frequency pulsetrain M_(j) matched to the actual value of the amplitude A_(j).

5.1.2.2.2.2. Slow Regulation Control:

The above given parameters M^(min) and C can be set either manually oradjusted for the device according to the invention in the course of slowregulation.

The slow regulation can occur over a time scale which preferablycorresponds to a period between 10 and 100 periods of the feed backsignal. C and M^(min) can be varied upwardly and downwardly incombination as well as separately. The goal of this regulation is tosuppress the expression of the pathological feature in the time windowof the slow regulation. By a sufficient suppression of the pathologicalfeature, is to be understood a suppression of the feature below thethreshold described in Section 4.5 hereof. Preferably exclusively theparameter M^(min) is regulated.

5.2. At Least One Electrode does not Lie in the Neuron Population to beDesynchronized:

As described in Section 3.3 hereof, at least one electrode 2 may not belocated in the neuron population to be desynchronized. In the case of anelectron 2 which does not lie in the neuron population to bedesynchronized, the neuron population to be desynchronized is influencedby indirect stimulation as described in Section 3.3 above. Since in thecase of an indirect stimulation, the conduction time between thestimulated neuron population on the one hand and the neuron populationto be desynchronized on the other can have various values, beforecarrying out the desynchronization stimulation the respective conductiontime is first measured. For this purpose the respective stimulationelectrode 2 is stimulated and the stimulation response is measured viathe electrodes which has been planted in the neuron population to bedesynchronized (sensor 3). This electrode is stimulated indirectly byall of the stimulation electrode 2 and thus separately n times whereby ntypically is a small whole number up to for example 200. From this themean conduction time is estimated advantageously in the followingmanner. The duration between the beginning of the stimulus applicationover the j^(th) electrode 2 and the first maximum of the stimulationresponse or the magnitude of the stimulation response, τ_(j) ^((k)) isdetermined for each individual stimulus application. In the magnitudeτ_(j) ^((k)) the index j stands for the j^(th) electrode 2 while theindex k stands for the tape applied stimulus. From this, for eachstimulation electrode 2 which is to effect an indirect stimulus,separately the mean duration between stimulus beginning and stimulusresponse is determined in accordance with Formula 4:

$\begin{matrix}{\tau_{j} = {\frac{1}{L_{j}}{\sum\limits_{k = 1}^{L_{j}}\tau_{j}^{(k)}}}} & {{Formula}\mspace{14mu} 4}\end{matrix}$

In this Formula, L_(j) represents the number of applied stimuli over thej^(th) stimulation electrode 2. L_(j) can, although not necessarily, bethe same for all stimulation electrodes 2 through which indirectstimulation is to be effected. The conduction time τ _(j) determined inthis manner for the desynchronizing stimulation, is taken intoconsideration in the following manner:

If in the direct synchronization of the neuron population to bedesynchronized, a stimulation is to be applied at time t over the j^(th)stimulation electrode, then in the case of the indirect stimulation thej^(th) stimulation electrode 2 will receive the stimulus at the time t−τ _(j).

The determination of the stimulation parameter at the beginning ofstimulation and the control mechanism during stimulation are fullyanalogous in the case where the conduction time τ _(j) is taken intoconsideration as described in Section 5.1.1 and 5.1.2 above.

5.3 Determination of the Threshold:

The parameters of the threshold described in Section 4.5 above must beselected for the demand controlled timing described for the embodimentin Section 4.3 above. In a preferred embodiment of the demand control,the threshold is either rendered intra operative or preferablydetermined in the first days after the operation by measuring the feedback signal over sensor 3, which is responsive to the expression of theillness specific feature, and comparing it with the expression of thesensor, for example, the degree of trembling. In a preferred embodimentthe selection of the threshold is monitored at significant timeintervals, for example, with half yearly monitoring. In a less preferredembodiment of the demand control timing, as the threshold arepresentative value, for example, a mean value of thresholds measuredwith a collection of patients is used.

5.4 Advantages

The calibration carried out in accordance with the invention is, bycomparison with the described calibration in German patent application102 11 766.7 substantially more rapid, less prone to failure and lessexpensive. It is clearly quicker since with direct stimulation withouttest stimuli the stimulation effect is immediately commenced andoptimized as described in Section 5.1.2 hereof. With repeatedstimulation with demand control stimulation strength and directstimulation of the neuron populations to be desynchronized, nocalibration is necessary. By contrast to this, in application DE 102 11766.7, the method requires a series of tests stimulation in which thestimulation parameter is systematically varied. By contrast thereto, forconduction time determination even in the case of the indirectstimulation described above, the duration is typically less than twominutes. According to the invention at least a half hour of time issaved by comparison with the prior art calibration. Because of the morerapid calibration, the method of the invention can be used intraoperatively and optimized during the placing of the deep electrodes 2.It is possible in this manner to use the affect of the desynchronizingstimulation on the expression of the sensor, for example, the tremordirectly as a parameter for the correctness of electrode placement.

The calibration in accordance with the invention is less prone tofailure by comparison with the calibration method of the German patentapplication 102 11 766.7 since the frequency and conduction timeestimation used in accordance with the calibration of the invention arenot treated as critical parameters as for example the limits andcharacteristics of the band path filter. By contrast, the calibration inthe German patent application 102 11 766.7 depends critically on theparameters of the band path filter used.

In addition, the calibration according to the invention utilizesfrequency and conduction time estimation which can be carried out withsignificantly simpler algorithms. As a consequence, the software andhardware realization is significantly less expensive.

Especially advantageous is the embodiment with repeated application withneed control stimulation strength since with this method no thresholdneed be detected. In contrast thereto, the embodiment using needcontrolled timing and also the method of German patent application DE102 11 766.7 requires threshold detection.

EXAMPLE

If for example four locations are to be stimulated, by means of fourelectrodes the following exemplary stimuli are produced:

1. With each of the electrodes the same high frequency pulse train isapplied whereby, as shown in FIGS. 5 a-5 d the pulse train are eachoffset in time by T/4 where T is the mean period of the rhythm to bedesynchronized.

2. Through the electrodes 1 and 2 high pulse trains of the same lengthbut different polarity are applied as shown in FIGS. 4 a-4 d. Throughthe electrodes 3 and 4 the same high frequency pulse train are appliedand for the electrodes 1 and 3 as well as 2 and 4, the same highfrequency pulse train are used. The high frequency pulse train of theelectrodes 3 and 4 are offset in time by T/4 (that is later) than thehigh frequency pulse trains of the electrodes 3 and 4.

Instead of the high frequency pulse train, also single pulses or lowfrequency pulse trains (with a frequency in the range of frequency ofthe neuron population to be desynchronized, is used). There are, by wayof example, two different control mechanisms with which a demand controland thus energy saving and mild (side-effect avoiding) stimulation canbe carried out:

1. Demand control (that is demand control selection of the time point)for the application of the total stimulus (FIG. 2):

Whenever the synchronization of the nerve cell population exceeds athreshold value, the next total stimulation is outputted over allelectrodes. This variant can be used preferentially when the rythme tobe suppressed does not fluate too greatly.

2. Repeated stimulation with demand control duration for the highfrequency pulse train (FIG. 3):

A periodic stimulation is carried out with coordinated stimulus throughall electrodes. The strength of the stimulus, that is preferably theduration of the high frequency pulse train, is matched to the strengthof the synchronization of the neuron population. The stronger thesynchronization the stronger the coordinated stimulus. With thisvariant, one can select a time delay between the individual stimuli atτ/ or rather than T/4 where T is the period of the rythme withoutstimulation and τ the period forced on the rythme by the stimulation. Inother words, τ is the frequency with which the individual stimuli areapplied. The result is a forced oscillation of the system using thesingle critical stimulation parameter. Instead of an expensivecalibration in this context it is dictated by the stimulation period.The demand control stimulation is utilized in any event since theneurons have a pathological tendency to fire periodically or in first(rythmic production of groups of action potential). Because of this anentrainment easily can arise, that is it is simple in subpopulations tostabilize the periodic rythme. Because of this this form of stimulationrequires about 1.5 times less current by comparison to demand controltiming.

In both controlled methods (demand control timing and demand controlstrength), one can preferably match the single important stimulationparameter, the time delay between the individual stimuli, by measurementof the frequency of the nerve cell population in the target reach oranother associated closely nerve cell population. In this case as wellmethod 2 (demand control strength) has the advantage that itsdesynchronizing effects is stable against small errors in the frequencyestimation or abrupt fluctuations of the frequency period.

The lack of a time consuming calibration and the stability of the effecteven in the case of strong frequency fluctuations, especially the method2 (demand controlled strength) has important consequencies:

1. Already intraoperatively it is possible during the insertion of thedeep electrode to apply the stimulation sequence and thereby monitor theeffect. As a consequence, the most suitable target point can bedetermined more clearly. For the prior demand control processes, onerequired a calibration which lasted thirty minutes longer per electrode.This is not suitable for an intraoperative procedure and cannot betolerated by a nonnarcatosized patient.

2. The new stimulation method allows the method to be utilized withneurological or psychiatric illnesses, in which the pathological rythmeare subject to strongly varying frequencies. Especially the new methodcan be used to desynchronize even intermittent (that is briefly arising)rythmes. The new stimulation method thus can be employed for a greatervariety of illnesses, above all even in the case of epilepsy.

With the device according to the invention with the new stimulationmethod, the following illnesses or symptoms can be alleviated by thedesynchronization of suitable framed areas. In all neurological andpsychiatric illnesses in which pathologically synchronized neuronalactivity plays a roll for the expression of the illness specificsymptom, for example, parkinsonism, essential tremor, dystony, obsessivedisorders, tremor in the case of multiple scolisis, tremor in the caseof impact accident or the like, for example tumorus tissue damage, forexample in the region of the thalamus and/or the basil ganglia,choreoathetosis and epilepsy, although this listing should not beconsidered as limiting.

By the standard measures used to date, the high frequency continuousstimulation, the following target areas are for example used:

In the case of parkinsonism, the nucleus subthalamicus or in the case oftremor dominant parkinsonism, the thalamus, for example, the nucleusventralis intermetius thalami. In the case of essential tremor, thethalamus, for example, the nucleus ventralis intermetius thalami. In thecase of dystony and choreoathetose the globus pallidum internum. Withepilepsy, the nucleus subthalamicus, the seraberum, the thalamic nuclearregion, for example the nucleus ventralis intermetius thalami or thenucleus caudatus. With obsessive disorder, the capsula interna or thenucleus accumbens.

With the device of the invention, by way of example, the target areaslisted above for the respective illnesses can be selected. With thedevice of the invention, even no calibration is required or thecalibration can be carried out more quickly. Thus providing thepossibility of allowing alternative target areas to be tested during theelectrode implantation so that the desynchronizing effect of the deviceof the invention can be more effective.

The invention also encompasses a control which controls and carries outthe required functions with the device according to the invention aswell as the use of the device and the control for the treatment ofparkinsonism, essential tremor, dystony, obsessive disorder,choreoathetose, tremor with multiple scolisis, tremor in the case ofimpact injuries or another, for example, tumorus tissue damage forexample in the region of the thalamus and/or the basalganglien, andepilepsy.

The device of the invention can be used as an implant for continuoustherapy of the above mentioned neurological and psychiatric illnesses aswell as for the intraoperative target point diagnostic, that is theintraoperative determination of the optical target point for theelectrode implantation.

1. A device for desynchronizing neuronal brain activity involving a neuron population firing in a synchronized manner at a pathological frequency, the device comprising: an electrode configured to generate stimuli that stimulate the neuron population; and a control unit configured to control the electrode to generate the stimuli in sequence, wherein the stimuli succeed each other with a predetermined frequency f, wherein the predetermined frequency f is substantially equal to g×n/m, and wherein g is the pathological frequency, and n and m are integers.
 2. The device of claim 1, wherein n is
 1. 3. The device of claim 1, wherein n is 1, 2 or 3, and m is 1, 2 or
 3. 4. The device of claim 1, wherein the stimuli are bursts of electrical pulses.
 5. The device of claim 1, wherein the electrode is further configured to generate the stimuli periodically.
 6. The device of claim 1, wherein the electrode is further configured to vary the generation of the stimuli stochastically and/or deterministically.
 7. The device of claim 1, wherein the device comprises a further electrode configured to generate stimuli that stimulates the neuron population, and wherein the control unit is further configured to control the further electrode to generate the stimuli in sequence, wherein the stimuli succeed each other with the predetermined frequency f.
 8. The device of claim 7, wherein the electrode and the further electrode are further configured to generate the stimuli simultaneously and with different polarities.
 9. The device of claim 7, wherein the electrode and the further electrode are further configured to generate the stimuli having a predetermined time shift between the stimuli generated by the electrode and the stimuli generated by the further electrode, wherein the stimuli generated by the electrode and the further electrode have the same polarities.
 10. The device of claim 7, wherein the electrode and the further electrode are configured to generate identical stimuli.
 11. The device of claim 4, wherein the control unit is further configured to vary when the electrical pulses in the bursts are generated either stochastically and/or deterministically. 